Environmental exposures to airborne carcinogens are the main etiological factors for lung cancers. Air pollutants such as nickel compounds pose significant risk for developing lung cancer in human. HIF-1 is a master regulator of the cellular hypoxic responses that promotes angiogenesis and cellular adaptation to hypoxia. It is also an important mediator of tumorigenesis and tumor progression. PTEN is an important tumor suppressor that negatively regulates the PI3K signaling pathway. The PI3K pathway mediates cell proliferation, growth, and survival thereby promoting tumorigenesis and tumor progression. Mutations and/or deletions of PTEN are frequently associated with human cancers. Thus, regulators of HIF-1 and PTEN are of great importance in tumor biology. Previous research has linked Plk3 to tumorigenesis and tumor progression. Our recent studies revealed direct regulations of HIF-1 and PTEN by Plk3. These findings suggest that Plk3 may act as a tumor suppressor that inhibits tumorigenesis and tumor progression by reducing cellular proliferative, growth, survival, and angiogenic processes. Of note, reduced expression of Plk3 has been reported in lung carcinomas. Based on these findings, we hypothesize that Plk3 suppresses nickel-induced tumorigenesis and tumor progression in the lung through regulating HIF-1 and PTEN. We propose two Specific Aims to test this hypothesis: Aim 1. To define the role of Plk3 in nickel-induced lung tumorigenesis in mouse models. Aim 2. To determine the role of Plk3 in nickel-induced lung epithelial cell transformation and tumor formation. These Specific Aims are designed to answer two basic questions: 1. Is Plk3 a significant player in lung carcinogenesis induced by nickel compounds? 2. How may Plk3 regulate lung tumorigenesis induced by nickel compounds through the newly identified regulatory mechanisms? We will combine approaches using mouse models and molecular/cellular biology to address these questions. This study should significantly advance our understanding of lung carcinogenesis in response to nickel compounds, the biology of Plk3, as well as the basic regulation of HIF-1 and PTEN. It will also serve as an initial evaluation of the potential of Plk3 as a therapeutic target.